The BET Protein Inhibitor Apabetalone Rescues Diabetes-Induced Impairment of Angiogenic Response by Epigenetic Regulation of Thrombospondin-1.

Aims: Therapeutic modulation of blood vessel growth holds promise for the prevention of limb ischemia in diabetic (DM) patients with peripheral artery disease (PAD). Epigenetic changes, namely, posttranslational histone modifications, participate in angiogenic response suggesting that chromatin-modifying drugs could be beneficial in this setting. Apabetalone (APA), a selective inhibitor of bromodomain (BRD) and bromodomain and extraterminal containing protein family (BET) proteins, prevents bromodomain-containing protein 4 (BRD4) interactions with chromatin thus modulating transcriptional programs in different organs. We sought to investigate whether APA affects angiogenic response in diabetes. Results: Compared with vehicle, APA restored tube formation and migration in human aortic endothelial cells (HAECs) exposed to high-glucose (HG) levels. Expression profiling of angiogenesis genes showed that APA prevents HG-induced upregulation of the antiangiogenic molecule thrombospondin-1 (THBS1). ChIP-seq and chromatin immunoprecipitation (ChIP) assays in HG-treated HAECs showed the enrichment of both BRD4 and active marks (H3K27ac) on THBS1 promoter, whereas BRD4 inhibition by APA prevented chromatin accessibility and THBS1 transcription. Mechanistically, we show that THBS1 inhibits angiogenesis by suppressing vascular endothelial growth factor A (VEGFA) signaling, while APA prevents these detrimental changes. In diabetic mice with hind limb ischemia, epigenetic editing by APA restored the THBS1/VEGFA axis, thus improving limb vascularization and perfusion, compared with vehicle-treated animals. Finally, epigenetic regulation of THBS1 by BRD4/H3K27ac was also reported in DM patients with PAD compared with nondiabetic controls. Innovation: This is the first study showing that BET protein inhibition by APA restores angiogenic response in experimental diabetes. Conclusions: Our findings set the stage for preclinical studies and exploratory clinical trials testing APA in diabetic PAD. Antioxid. Redox Signal. 36, 667-684.

Long-term follow-up of tibiocalcaneal arthrodesis in diabetic patients with early chronic Charcot osteoarthropathy.

Charcot osteoarthropathy with severe ankle instability and deformity is often managed with below-the-knee amputation if deformity and cutaneous compromise result in osteomyelitis. Recently, some surgeons have reported satisfactory outcomes with ankle arthrodesis in the coalescence or remodeling (subacute and chronic) stages of the disease before the onset of joint instability, severe deformity, and ulcer formation. This observational study describes the clinical outcomes of ankle arthrodesis in a cohort of 45 diabetic patients who underwent unilateral ankle arthrodesis for Charcot neuroarthropathic ankle deformity before the development of ulceration and bone infection. Two (4.44%) of the patients were lost to follow-up, whereas 2 (4.44%) others underwent below-the-knee amputation shortly after the ankle arthrodesis because of postoperative infection. After a mean follow-up duration of 5 ± 2.85 years, 39 (86.67%) patients returned to independent ambulation wearing custom-made shoes with molded insoles, whereas 2 (4.44%) others required pneumatic casts for ambulation.